Referenced in: none

Automatically associated channels: ClC4 , ClCA1 , ClCA3

Title: Niflumic acid suppresses interleukin-13-induced asthma phenotypes.

Authors: Takako Nakano, Hiromasa Inoue, Satoru Fukuyama, Koichiro Matsumoto, Mikiko Matsumura, Miyuki Tsuda, Takafumi Matsumoto, Hisamichi Aizawa, Yoichi Nakanishi

Journal, date & volume: Am. J. Respir. Crit. Care Med., 2006 Jun 1 , 173, 1216-21

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16528019

Abstract
Chloride channels have been implicated in the regulation of mucus production in epithelial cells. Expression of hCLCA1, a calcium-activated chloride channel, has been reported to be increased in the airway epithelium of patients with asthma. Interleukin (IL)-13 induces the cardinal features of bronchial asthma, and glucocorticoids are not sufficient to suppress IL-13-induced airway hyperresponsiveness or goblet cell hyperplasia.We studied the effects of chloride channel inhibitors in IL-13-induced asthma.The effects of niflumic acid (NA), a relatively specific blocker of calcium-activated chloride channel (CLCA), on goblet cell hyperplasia, eosinophil accumulation, and airway hyperresponsiveness were evaluated after IL-13 instillation into the airways. Because IL-13-dependent features rely on JAK/STAT6 signaling, the effect of NA on phosphorylation of JAK2 and STAT6 after IL-13 stimulation was examined in airway epithelial cells in vitro. The expression of the mCLCA family in mouse lung after IL-13 local administration in vivo was analyzed using reverse transcription-polymerase chain reaction.Treatment with NA inhibited not only IL-13-induced goblet cell hyperplasia but also airway hyperresponsiveness and eosinophilic infiltration. NA suppressed the eotaxin levels in bronchoalveolar lavage fluids and overexpression of the MUC5AC gene, a marker of goblet cell hyperplasia, in the lung after IL-13 instillation. NA suppressed JAK2 activation, STAT6 activation, and eotaxin expression in epithelial cells. The expression of mCLCA3 (mouse homolog hCLCA1), but not that of other CLCA family members, was up-regulated by IL-13.These findings suggest that a chloride channel inhibitor can control IL-13-mediated airway features at least by suppressing JAK/STAT6 activation.